Novel compounds for treatment of cardiac arrhythmia and methods of use

ABSTRACT

The subject invention provides novel compounds for treatment of cardiac arrhythmia and methods of use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/560,917, filed Apr. 9, 2004.

BACKGROUND OF INVENTION

1. Field of the Invention

This invention relates to the field of treatment of cardiac arrhythmiaand, in particular, new compounds and associated methods useful in suchtreatments.

SUMMARY OF RELATED ART

Congestive heart failure (CHF) is a disease affecting approximately 2%of the population of the United States (Sami, M. H. [1991] J. Clin.Pharmacol. 31:1081). Despite advances in the diagnosis and treatment ofCHF, the prognosis remains poor with a 5-year mortality rate higher than50% from the time of diagnosis (McFate Smith, W. [1985] Am. J. Cardiol.55:3A; McKee, P. A., W. P. Castelli, P. M. McNamara, W. B. Kannel [1971]N. Engl. J. Med. 285:1441). In patients with CHF, the rate of survivalis lowest in those patients with severe depression of left ventricularfunction and patients who have frequent ventricular arrhythmias.Patients with ventricular arrhythmias and ischemic cardiomyopathy havean increased risk of sudden death. The presence of ventriculartachycardia in patients with severe CHF results in a three-fold increasein sudden death compared to those without tachycardia (Bigger, J. T.,Jr. [1987] Circulation 75 (Supplement IV):28). Because of the highprevalence of sudden unexpected death in patients with CHF, there hasbeen a growing interest in the prognostic significance of arrhythmias inthese patients.

Several compounds have been used in the management of cardiacarrhythmias in patients with congestive heart failure. Unfortunately,anti-arrhythmic drug therapy has been disappointing. The efficacy ofanti-arrhythmic drugs markedly decreases as left ventricular functiondeclines, such that only a small fraction of patients with CHF areresponsive to anti-arrhythmic therapy. No anti-arrhythmic drug hasprevented sudden death in patients with CHF. There is even a question ofincreased mortality associated with certain anti-arrhythmic drugs (theCAST investigators [1989] N. Engl. J. Med. 321:406).

Scientists define tachycardia and ventricular fibrillation as being ofmultiple nature. It now seems clear, and is accepted in the art, thatre-entry is the underlying mechanism to most sustained arrhythmias.Prolonging ventricular repolarization as a means of preventingventricular arrhythmias has consequently received renewed attention.This points to Class-III agents as drugs of choice in the treatment ofarrhythmias. A Class-III agent, as referred to herein, is an agent whichis classified as such in the Vaughan-Williams classification ofanti-arrhythmic drugs. A Class-III agent exerts its primaryanti-arrhythmic activity by prolonging cardiac action potential duration(APD), and thereby the effective refractory period (ERP), with no effecton conduction. These electrophysiological changes, which are broughtabout by blockade of cardiac potassium channels, are well known in theart. Because the blockade of cardiac potassium channels is notassociated with depression of the contractile function of the heart,Class-III agents are particularly attractive for use in patients withCHF. Unfortunately, the existing Class-III agents are limited in theirutility by additional pharmacological activities, lack of good oralbioavailability, or a poor toxicity profile. The only two Class IIIagents currently marketed are bretylium (i.v. only) and amiodarone (i.v.and p.o.).

Amiodarone is an anti-arrhythmic agent having vasodilator propertiesthat may benefit patients with severe heart failure. Amiodarone has beenshown to improve survival of post-myocardial infarction patients withasymptomatic high-grade ventricular arrhythmias, and it provedefficacious in patients resistant to other anti-arrhythmic drugs withoutimpairing left ventricular function. Cardioprotective agents and methodswhich employ amiodarone in synergistic combination with vasodilators andbeta blockers have been described for use in patients with coronaryinsufficiency (U.S. Pat. No. 5,175,187). Amiodarone has also beendescribed for reducing arrhythmias associated with CHF as used incombination with antihypertensive agents, e.g.,(S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-L-proline (U.S.Pat. No. 4,962,095) and zofenopril (U.S. Pat. No. 4,931,464). However,amiodarone is a difficult drug to manage because of its numerous sideeffects, some of which are serious.

The most serious long-term toxicity of amiodarone derives from itskinetics of distribution and elimination. It is absorbed slowly, with alow bioavailability and relatively long half-life. These characteristicshave clinically important consequences, including the necessity ofgiving loading doses, a delay in the achievement of full anti-arrhythmiceffects, and a protracted period of elimination of the drug after itsadministration has been discontinued.

Amiodarone also can interact negatively with numerous drugs includingaprindine, digoxin, flecainide, phenytoin, procainamide, quinidine, andwarfarin. It also has pharmacodynamic interactions with catecholamines,diltiazem, propranolol, and quinidine, resulting in alpha- andbeta-antagonism, sinus arrest and hypotension, bradycardia and sinusarrest, and torsades de pointes and ventricular tachycardias,respectively. There is also evidence that amiodarone depresses vitaminK-dependent clofting factors, thereby enhancing the anticoagulant effectof warfarin.

Numerous adverse effects limit the clinical applicability of amiodarone.Important side effects can occur including corneal microdeposits,hyperthyroidism, hypothyroidism, hepatic dysfunction, pulmonaryalveolitis, photosensitivity, dermatitis, bluish discoloration, andperipheral neuropathy.

Compounds of structural formula I:

and pharmaceutically acceptable salts thereof, wherein m is 0 to 4, n is0 or 1, X₁ and X₂ are H, lower alkyl, or halogen, preferably iodine, R₁and R₂ are lower alkyl, and R₃ is optionally substituted alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. PreferablyR₃ is (R)-2-butyl, (S)-2-butyl, (R)-3-methyl-2-butyl, or(S)-3-methyl-2-butyl.

The preferred compounds have the following formulas

and include pharmaceutically acceptable salts thereof. Particularlypreferred salts are citrate, (L)-tartrate, (D)-tartrate, fumarate,maleate. These compounds are useful for treating mammals, includinghumans, suffering from ventricular and supraventricular arrhythmias,including atrial fibrillation.

These compounds, when administered to a mammal, including a human, giverise to metabolites that are useful for drug monitoring and that haveelectrophysiological properties of their own.

There is no Class-II agent presently marketed that can be used safely inpatients with CHF. The cardiovascular drug market is the largest in anyfield of drug research, and an effective and safe Class-IIanti-arrhythmic agent useful in patients with CHF is expected to be ofsubstantial benefit. Therefore, a drug which could successfully improvethe prognosis of CHF patients, but with a safety profile much improvedover that of amiodarone, would be extremely useful and desired. Variousanalogs of amiodarone have been previously described (U.S. Pat. Nos.6,710,070; 6,683,195; 6,372,783; 6,362,223; 6,316,487; 6,130,240;5,849,788; 5,440,054; and 5,364,880). The subject invention adds to thisarsenal of compounds.

SUMMARY OF THE INVENTION

The present invention provides compounds that have particular utilityfor treating life-threatening ventricular tachyarrhythmias, especiallyin patients with congestive heart failure (CHF). The compounds of thesubject invention also provide effective management for ventriculararrhythmias and supraventricular arrhythmias, including atrialfibrillation and re-entrant tachyarrhythmias involving accessorypathways.

More specifically, the novel compounds have the particular advantage ofreducing the numerous side effects observed with the drugs currentlyavailable for treatment of these cardiac arrhythmias. For example, thecompound of choice currently used for treating cardiac arrhythmias isamiodarone, which has side effects that can be serious. Becausecompounds of the invention are metabolites of compounds such as 1 to 4,they can be used for therapeutic drug monitoring in patients receivingtherapeutic doses of compounds 1 to 4. An example is given in scheme 1below where the metabolism of compound 1 is shown.

Scheme 1 depicts the metabolism of compound 1 in animals, includinghumans. “A” denotes an ester cleavage metabolic reaction, and “B”denotes a N-dealkylation reaction. Scheme 1 shows that the parent drug,i.e., compound 1, can either undergo an ester cleavage metabolicreaction to compound 5, or can undergo a N-desethylation reaction tocompound 6, which itself can undergo ester cleavage to compound 7, orN-desethylation to compound 8, which in turn can be cleaved by esterasesto compound 9. Scheme 1 is given as an illustrative example. However,the metabolic scheme for compounds 2, 3, and 4 is similar to the schemefor compound 1.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the time course of effect of Compound 6 (1 μM) onIntra-Atrial Conduction (S-A Interval).

FIG. 2 shows the Time Course of Effect of Compound 6 (1 μM) on AV NodalConduction (A-H Interval).

FIG. 3 shows the Time Course of Effect of Compound 6 (1 μM) onHis-Purkinje Conduction (H-V Interval).

FIG. 4 shows the Time Course of Effect of Compound 6 (1 μM) onIntra-ventricular Conduction (QRS Interval).

FIG. 5 shows the Time Course of Effect of Compound 6 (1 μM) onVentricular Repolarization (Q-T Interval).

FIG. 6 shows the Time Course of Effect of Compound 6 (1 μM) onVentricular Repolarization (MAPD₉₀).

FIG. 7 shows the Time Course of Effect of Compound 7 (1 μM) onIntra-Atrial Conduction (S-A Interval).

FIG. 8 shows the Time Course of Effect of Compound 7 (1 μM) on AV nodalConduction (A-H Interval).

FIG. 9 shows the Time Course of Effect of Compound 7 (1 μM) onHis-Purkinje Conduction (H-V Interval).

FIG. 10 shows the Time Course of Effect of Compound 7 (1 μM) onIntral-ventricular Conduction (QRS Interval).

FIG. 11 shows the Time Course of Effect of Compound 7 (1 μM) onVentricular Repolarization (Q-T Interval).

FIG. 12 shows the Time Course of Effect of Compound 7 (1 μM) onVentricular Repolorization (MAPD₉₀).

DETAILED DISCLOSURE OF THE INVENTION

The subject invention provides novel compounds that can produce thedesired pharmacological properties of amiodarone, but do not have theundesirable physiological properties of amiodarone. Specifically,long-term toxicity symptoms (pulmonary fibrosis, corneal microdeposits,etc.) are reduced with the compounds of the subject invention. Inaddition, the novel compounds are metabolites of compounds of structuralformula I, such as compounds 1 to 4 when compounds 1 to 4 areadministered to a mammal, including a human. These compounds cantherefore be used to monitor drug levels and drug pharmacokinetics inpatients receiving compounds 1 to 4.

The present invention provides substantially pure compounds ofstructural formula II:

and pharmaceutically acceptable salts thereof, wherein

-   -   R₁ is H or C₁-C₁₀ alkyl;    -   R₂ is H or optionally substituted C₁-C₁₀ alkyl, heteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   n=0 to 4;    -   p=0 or 1;    -   R₃ and R₄ are, independently, H or C₁-C₄ alkyl.

By “substantially pure” is meant that the compounds contain less than20%, preferably less than 10%, and more preferably less than 5%impurities on a weight basis. (“Impurities” does not encompasspharmaceutically acceptable carriers, diluents, excipients, or thelike.)

In particularly preferred embodiments, R₁ is ethyl; R₂ is (S)-2-butyl,(R)-2-butyl, (S)-3-methyl-2-butyl, or (R)-3-methyl-2-butyl; n=0 or 1,most preferably n=1; p=0; and, R₃ and R₄ are, independently, H ormethyl.

Specifically exemplified herein are the following compounds (Compound 6through Compound 9):

Particularly preferred compounds include(S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester;{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid;(S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester;{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid;(R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester;(R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester;(S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester;(R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester;(S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester;(R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester.

The novel compounds can also be provided in their salt form. Thus, theinvention includes pharmaceutically acceptable salts, for example acidaddition salts derived from inorganic or organic acids, such ashydrochlorides, hydrobromides, p-toluenesulfonates, phosphates,sulfates, perchlorates, acetates, trifluororacetates, proprionates,citrates, malonates, succinates, lactates, oxalates, (L)-tartrates,(D)-tartrates, meso-tartrates, and benzoates. Salts may also be derivedfrom bases (organic and inorganic), such as alkali metal salts (e.g.,magnesium or calcium salts), or organic amine salts, such as morpholine,piperidine, dimethylamine, or diethylamine salts.

The compounds of the subject invention can be readily made by a personskilled in the art having the benefit of the current disclosure and, forexample, the disclosures in U.S. Pat. Nos. 6,710,070; 6,683,195;6,372,783; 6,362,223; 6,316,487; 6,130,240; 5,849,788; 5,440,054; and5,364,880. These patents are incorporated herein by reference.

Additional modifications of the compounds disclosed herein can readilybe made by those skilled in the art. Thus, analogs and salts of theexemplified compounds are within the scope of the subject invention.With knowledge of the compounds of the subject invention skilledchemists can use known procedures to synthesize these compounds fromavailable substrates. As used in this application, the term “analogs”refers to compounds which are substantially the same as another compoundbut which may have been modified by, for example, adding additional sidegroups. The term “analogs” as used in this application also may refer tocompounds which are substantially the same as another compound but whichhave atomic or molecular substitutions at certain locations in thecompound.

Analogs of the exemplified compounds can be readily prepared usingcommonly known, standard reactions. These standard reactions include,but are not limited to, hydrogenation, methylation, acetylation,halogenation, and acidification reactions. For example, new salts withinthe scope of the invention can be made by adding mineral acids, e.g.,HCl H₂SO₄, etc., or strong organic acids, e.g., formic, oxalic, etc., inappropriate amounts to form the acid addition salt of the parentcompound or its derivative. Also, synthesis type reactions may be usedpursuant to known procedures to add or modify various groups in theexemplified compounds to produce other compounds within the scope of theinvention.

The subject invention further pertains to enantiomerically isolatedcompounds, and compositions comprising the compounds, for calciumchannel blocking. The isolated enantiomeric forms of the compounds ofthe invention are substantially free from one another (i.e., inenantiomeric excess). In other words, the “R” forms of the compounds aresubstantially free from the “S” forms of the compounds and are, thus, inenantiomeric excess of the “S” forms. Conversely, “S” forms of thecompounds are substantially free of “R” forms of the compounds and are,thus, in enantiomeric excess of the “R” forms. In one embodiment of theinvention, the isolated enantiomeric compounds are at least about in 80%enantiomeric excess. In a preferred embodiment, the compounds are in atleast about 90% enantiomeric excess. In a more preferred embodiment, thecompounds are in at least about 95% enantiomeric excess. In an even morepreferred embodiment, the compounds are in at least about 97.5%enantiomeric excess. In a most preferred embodiment, the compounds arein at least 99% enantiomeric excess.

A further aspect of the subject invention pertains to the breakdownproducts which are produced when the therapeutic compounds of thesubject invention are acted upon by hydrolytic enzymes, such asesterases. The presence of these breakdown products in urine or serumcan be used to monitor the rate of clearance of the therapeutic compoundfrom a patient.

The successful application of the new compounds to the treatment of CHFis evidenced by the evaluation of the thermodynamic properties of thecompound, e.g., measuring its partition coefficient between water andoctanol, evaluation of its kinetics of elimination by measuring itsstability in buffer and in human plasma, and evaluation of itselectrophysiological properties in guinea pig heart preparations.

More specifically, the novel compounds can be used for treatinglife-threatening ventricular tachyarrhythmias, especially in patientswith congestive heart failure. Thus, the compounds of the subjectinvention provide effective management of not only ventriculartachyarrhythmias and less severe ventricular arrhythmias, but alsoatrial fibrillation and re-entrant tachyarrhythmias involving accessorypathways. A composition comprising a novel compound having a rapidelimination rate can offer many advantages over the currently availableanti-arrhythmic agents such as amiodarone.

These advantages include:

-   -   (i) a shorter onset of action,    -   (ii) decreased and more manageable long-term toxicity, and    -   (iii) lower potential for drug-drug interactions.

In addition, the novel compounds can be included in a compositioncomprising a second active ingredient. The second active ingredient canbe useful for concurrent or synergistic treatment of arrhythmia or forthe treatment of an unrelated condition which can be present with orresult from arrhythmia or CHF.

The subject compounds have thermodynamic properties similar to those ofamiodarone, but provide the advantageous property of being rapidlymetabolized in plasma to a water-soluble metabolite. More specifically,the subject compounds are Class-II agents with electronic, steric, andthermodynamic properties comparable to those of amiodarone, but with anenzymatically labile ester group advantageously built into the structuresuch that the drug can be readily hydrolyzed in plasma to a polar,water-soluble metabolite. This water-soluble metabolite can beeliminated by the kidneys. This is a definite advantage over amiodarone,which is metabolized primarily in the liver. Under such conditions, theelimination of the novel compounds are increased and results in a morerapid dissociation of the drug from phospholipid-binding sites. Theaccumulation of the compound, which is dependent on the steady-statetissue concentration of the drug, and therefore on the dose, thenbecomes easily reversible. It follows that, upon discontinuation of adrug comprising one of the novel compounds, clearance from the body ismore rapid. This increased elimination makes anti-arrhythmic therapyusing the subject compounds or compositions comprising the subjectcompounds easier to manage.

Furthermore, the compounds of the invention may be administered inconjunction with other compounds, or compositions thereof. Thesecompounds, and compositions thereof, may include additional compoundsknown to be useful for the treatment of cardiac arrhythmias,cardioprotective agents, antibiotics, antiviral agents, or thrombolyticagents (e.g., streptokinase, tissue plasminogen activator, orrecombinant tissue plasminogen activator). The compounds andcompositions of the invention can have particular usefulness fortreating life-threatening ventricular tachyarrhythmias, especially inpatients with congestive heart failure (CHF). Post-myocardial infarctionpatients can also benefit from the administration of the subjectcompounds and compositions; thus, methods of treating post- myocardialinfarction patients are also provided by the subject invention. An“individual” or “patient” includes animals and humans in need oftreatment for arrhythmias. In a preferred embodiment, the individual isa human.

Cardioprotective agents include vasodilators and beta blockers describedfor use in patients with coronary insufficiency (such as those of U.S.Pat. No. 5,175,187 or others known to the skilled artisan). Othercardioprotective agents include known anti-hypertensive agents, e.g.,(S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxyl]-L-proline(U.S. Pat. No. 4,962,095) and zofenopril (U.S. Pat. No. 4,931,464).Additional cardioprotective agents include, but are not limited to,aspirin, heparin, warfarin, digitalis, digitoxin, nitroglycerin,isosorbide dinitrate, hydralazine, nitroprusside, captopril, enalapril,and lisinopril.

The compounds and compositions also provide effective management forventricular arrhythmias and supraventricular arrhythmias, includingatrial fibrillation and re-entrant tachyarrhythmias involving accessorypathways. Compounds and compositions of the invention are also usefulfor the treatment of ventricular and supra-ventricular arrhythmias,including atrial fibrillation and flutter, paroxysmal supraventriculartachycardia, ventricular premature beats (VPB), sustained andnon-sustained ventricular tachycardia (VT), and ventricular fibrillation(VF). Other non-limiting examples of the arrhythmias which may betreated by the compounds of the instant invention include: narrow QRStachycardia (atrial, intra- /para- A-V node, or accessory pathway),ventricular tachycardia, and ventricular arrhythmias in cardiomyopathy.

The compounds of this invention have therapeutic properties similar tothose of the unmodified parent compounds. Accordingly, dosage rates androutes of administration of the disclosed compounds are similar to thosealready used in the art and known to the skilled artisan. (See, forexample, Physicians' Desk Reference. 54^(th) Ed., Medical EconomicsCompany, Montvale, N.J., 2000.)

The compounds of the subject invention can be formulated according toknown methods for preparing pharmaceutically useful compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulation which can be used in connection with the subject invention.In general, the compositions of the subject invention are formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith a suitable carrier in order to facilitate effective administrationof the composition.

In accordance with the subject invention, pharmaceutical compositionsare provided which comprise, as an active ingredient, an effectiveamount of one or more of the compounds and one or more non-toxic,pharmaceutically acceptable carriers or diluents. Examples of suchcarriers for use in the invention include ethanol, dimethyl sulfoxide,glycerol, silica, alumina, starch, and equivalent carriers and diluents.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances that may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or encapsulating materials.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenges.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃-CH₂—) certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂-CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B-, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B- and when a is 1 the moiety isA-B-.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8carbon atoms, and more preferably 1-6 carbon atoms, which is optionallysubstituted with one, two or three substituents. Preferred alkyl groupsinclude, without limitation, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃alkyl”) is a covalent bond (like “C₀” hydrocarbyl). As used herein“lower alkyl” means an alkyl moiety of 1 to 6 carbons.

The term “alkenyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl,or alkynyl group, as defined hereinabove, that is positioned between andserves to connect two other chemical groups. Preferred alkylene groupsinclude, without limitation, methylene, ethylene, propylene, andbutylene. Preferred alkenylene groups include, without limitation,ethenylene, propenylene, and butenylene. Preferred alkynylene groupsinclude, without limitation, ethynylene, propynylene, and butynylene.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, and N.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. Preferably, the arylgroup is a C₆-C₁₀ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl”or “arylalkyl” group comprises an aryl group covalently linked to analkyl group, either of which may independently be optionally substitutedor unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

A “heterocyclic” group (alternatively referred to as “heterocyclyl” or“heterocycloalkyl”) is an optionally substituted non-aromatic mono-,bi-, or tricyclic structure having from about 3 to about 14 atoms,wherein one or more atoms are selected from the group consisting of N,O, and S. One ring of a bicyclic heterocycle or two rings of a tricyclicheterocycle may be aromatic, as in indan and 9,10-dihydro anthracene.The heterocyclic group is optionally substituted on carbon with oxo orwith one of the substituents listed above. The heterocyclic group mayalso independently be substituted on nitrogen with alkyl, aryl, aralkyl,alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl,alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl.Preferred heterocyclic groups include, without limitation, epoxy,aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certainpreferred embodiments, the heterocyclic group is fused to an aryl,heteroaryl, or cycloalkyl group. Examples of such fused heterocyclesinclude, without limitation, tetrahydroquinoline and dihydrobenzofuran.Specifically excluded from the scope of this term are compounds where anannular O or S atom is adjacent to another O or S atom.

As used herein, the term “heteroaryl” refers to optionally substitutedgroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 pi electrons shared in a cyclic array; and having,in addition to carbon atoms, between one or more heteroatoms selectedfrom the group consisting of N, O, and S. For example, a heteroarylgroup may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl,benzothiazolyl, benzofuranyl and indolinyl. Preferred heteroaryl groupsinclude, without limitation, thienyl, benzothienyl, furyl, benzofuryl,dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl,oxazolyl, thiazolyl, triazolyl, and isoxazolyl.

A “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroarylgroup covalently linked to an alkyl group, either of which isindependently optionally substituted or unsubstituted. Preferredheteroalkyl groups comprise a C₁-C₆ alkyl group and a heteroaryl grouphaving 5, 6, 9, or 10 ring atoms. Specifically excluded from the scopeof this term are compounds having adjacent annular O and/or S atoms.Examples of preferred heteroaralkyl groups include pyridylmethyl,pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,imidazolylethyl, thiazolylmethyl, and thiazolylethyl.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an aryl,heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH-substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl,aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl,sulfonamido, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido,alkylcarbonyl, acyloxy, cyano, alkylthio, ureido, and ureidoalkylgroups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, alkyl, alkoxy, alkylthio, haloalkoxy,        aminoalkyl, aminoalkoxy, carboxy, formyl, nitro, amino, amidino,        carbamoyl, guanidino, C₃-C₇ heterocycle, heterocyclylalkyl,        heterocyclylcarbonyl, hydroxyalkyl, alkoxyalkyl,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl,        carbamate, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl,        alkylaryl, arylalkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈        acylamino, C₁-C₈ alkylthio, arylalkylthio, arylthio,        heteroarylthio, C₁-C₈ alkylsulfinyl, arylalkylsulfinyl,        arylsulfinyl, C₁-C₈ alkylsulfonyl, arylalkylsulfonyl,        arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        heteroaryloxy, arylalkyl ether, C₃-C₇ heterocyclylalkylether,        aryl, aryl fused to a cycloalkyl or heterocycle or another aryl        ring, C₃-C₇ heterocyclyl, heteroaryl, arylcarbamoyl, or any of        these rings fused or spiro-fused to a cycloalkyl, heterocyclyl,        or aryl, wherein any of the foregoing which are additionally        substitutable is further optionally substituted with one more        moieties listed in (a), above; and    -   (c) —(CH₂)_(S)—NR³⁰R³¹, wherein s is from 0 (in which case the        nitrogen is directly bonded to the moiety that is substituted)        to 6, and R³⁰ and R³¹ are each independently hydrogen, cyano,        oxo, carboxamido, amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl,        aryl-C₁-C₃ alkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C8 alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃        alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,        heterocyclyl, or heteroaryl, wherein each of the foregoing is        further optionally substituted with one more moieties listed in        (a), above; or

R³⁰ and R³¹ taken together with the N to which they are attached form aheterocyclyl or heteroaryl, each of which is optionally substituted withfrom 1 to 3 substituents from (a), above.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 9-14membered bi-cyclic moieties fused to the parent cyclic moiety to form abi- or tricyclic fused ring system. For example, an optionallysubstituted phenyl includes, but not limited to, the following:

Preferred substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) also include groups of the formula—K¹—N(H)(R¹⁰), wherein

K¹ is a C₀-C₄ alkylene;

R₁₀ is C₀-C₄ alkylene —Z′, and

Z′ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of whichoptionally is substituted, and each of which optionally is fused to oneor more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings.

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally optionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

Throughout the specification preferred embodiments of one or morechemical substituents are identified. Also preferred are combinations ofpreferred embodiments.

Some compounds of the invention may have chiral centers and/or geometricisomeric centers (E- and Z- isomers), and it is to be understood thatthe invention encompasses all such optical, diastereoisomers andgeometric isomers. The invention also comprises all tautomeric forms ofthe compounds disclosed herein. Where compounds of the invention includechiral centers, the invention encompasses the enantiomerically pureisomers of such compounds, the enantiomerically enriched mixtures ofsuch compounds, and the racemic mixtures of such compounds.

Following are examples that illustrate aspects of the subject invention.These examples should not be construed as limiting.

EXAMPLE 1 Electrophysiological Effects of Compound 6

The model used to test the electrophysiological properties of Compound 6utilized atrial-paced (cycle length=300 ms) guinea pig isolated heartsperfused with Krebs-Henseleit solution at 36° C. The followingrecordings were made:

Electrophysiological Recordings: atrial and His-bundle electrograms.

EP Measurements: SA, AH, HV, QRS and QT intervals.

Compound 6 was given via.infusion pump into perfusate line.Time-dependent EP effects were measured at 1 μM Compound 6. Compound 6lwas infused for 90 minutes, then washed for 90 minutes. EP measurementswere made Q 10 minutes. Data was analyzed by 1 way repeated measuresANOVA followed by SNK testing for multiple comparisons.

The results are presented in FIGS. 1-6.

EXAMPLE 2 Electrophysiological Effects of Compound 7

The model used to test the electrophysiological properties of Compound 7utilized atrial-paced (cycle length=300 ms) guinea pig isolated heartsperfused with Krebs-Henseleit solution at 36° C. The followingrecordings were made:

Electrophysiological Recordings: atrial and His-bundle electrograms.

EP Measurements: SA, AH, HV, QRS and QT intervals.

Compound 7 was given via infusion pump into perfusate line.Time-dependent EP effects were measured at 1 μM Compound 7. Compound 7was infused for 90 minutes, then washed for 90 minutes. EP measurementswere made Q 10 minutes. Data was analyzed by 1 way repeated measuresANOVA followed by SNK testing for multiple comparisons.

The results are presented in FIGS. 7-12.

EXAMPLE 3 Synthesis of Compounds

The compounds of the subject invention can be readily made, or isolated,by a person skilled in the art having the benefit of the currentdisclosure as well as, for example, the disclosures in U.S. Pat. Nos.6,710,070; 6,683,195; 6,372,783; 6,362,223; 6,316,487; 6,130,240;5,849,788; 5,440,054; and 5,364,880. Schemes 2 and 3 provide synthesisprocedures for making compounds 6 and 7 (examples where the ester moietyis (S)-2-butyl).

Specific reaction conditions can be readily determined by chemistsskilled in the art having the current disclosure. In addition, areasonably skilled chemist will recognize that the same synthetic schemecan be applied to make the compounds of the subject invention.

Scheme 2: (a) benzyl bromde/triethylamine (b) Tosylchloride/triethylamine

Scheme 3: (a) compound 12/KHCO₃/toluene/water (b) 1-chlorethylchloroformate/methanol (c) H₂SO₄

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication.

1. A substantially pure compound of structural formula II:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H or C₁-C₁₀alkyl; R₂ is H or optionally substituted C₁-C₁₀ alkyl, heteroalkyl,cycloalkyl, or heterocycloalkyl; n=0 to 4; p=0 or 1; R₃ and R₄ are,independently, H or C₁-C₄ alkyl.
 2. The compound according to claim 1wherein R₁ is ethyl; R₂ is (S)-2-butyl, (R)-2-butyl,(S)-3-methyl-2-butyl, or (R)-3-methyl-2-butyl; n=0 or 1, most preferablyn=1; p=0; and, R₃ and R₄ are, independently, H or methyl.
 3. Thecompound according to claim 2 wherein n is
 1. 4. The compound accordingto claim 1 selected from:


5. The compound according to claim 1 selected from a)(S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester; b){3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid; c)(S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester; d){3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid;e)(R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid sec-butyl ester; f)(R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-aceticacid sec-butyl ester; g)(S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester; h)(R)-3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester; i)(S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester; and j)(R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodobenzoyl]benzofuran-2-yl}-aceticacid 1,2-dimethyl-propyl ester.
 6. A composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier, diluent,or excipient.
 7. A composition comprising a compound according to claim2 and a pharmaceutically acceptable carrier, diluent, or excipient.
 8. Acomposition comprising a compound according to claim 3 and apharmaceutically acceptable carrier, diluent, or excipient.
 9. Acomposition comprising a compound according to claim 4 and apharmaceutically acceptable carrier, diluent, or excipient.
 10. Acomposition comprising a compound according to claim 5 and apharmaceutically acceptable carrier, diluent, or excipient.
 11. A methodof treating cardiac arrhythmias comprising administering to a patientexperiencing a cardiac arrhythmia an effective amount of a compositionaccording to claim
 6. 12. A method of treating cardiac arrhythmiascomprising administering to a patient experiencing a cardiac arrhythmiaan effective amount of a composition according to claim
 7. 13. A methodof treating cardiac arrhythmias comprising administering to a patientexperiencing a cardiac arrhythmia an effective amount of a compositionaccording to claim
 8. 14. A method of treating cardiac arrhythmiascomprising administering to a patient experiencing a cardiac arrhythmiaan effective amount of a composition according to claim
 9. 15. A methodof treating cardiac arrhythmias comprising administering to a patientexperiencing a cardiac arrhythmia an effective amount of a compositionaccording to claim 10.